ESPE Abstracts

Introduction: Single, large scale mitochondrial DNA (mtDNA) deletions (SLSMDs) comprise clinically heterogeneous group of rare and progressive multisystem disorders. Diverse initial symptoms, evolving and overlapping phenotype together with genetic heterogeneity pose a major challenge in diagnosis and treatment. We report on a young girl with SLSMD who presented with unique constellation of initial symptoms including diabetes mellitus (DM), macrocytosis, and skin pigmentation disorder thus providing valuable insight into the clinical spectrum of this disease with poorly understood natural history.

Case Report: A 3.2-year-old girl, a second child of healthy unrelated parents, born from uneventful pregnancy, was referred to us due to newly diagnosed insulin-dependent DM with negative beta cell autoantibodies. She presented with additional atypical findings: short stature, sparse hair, skin pigmentation anomalies (hypo/hyperpigmented patches) and macrocytic anemia. The anemia resolved spontaneously during the following months, but the macrocytosis persisted. The evaluation for potential hematological causes of macrocytosis yielded unremarkable results. Over time, she developed a series of other symptoms including intermittent photophobia and conjunctival injection, leading to a diagnosis of corneal dystrophy at the age of 5. Hearing impairment was noticed at 3.8 years and diagnosed as sensorineural hearing loss. At 4.2 years, she developed subcutaneous nodules on legs. A brain MRI performed at 4.5 years did not reveal any pathological changes. Although peripheral blood analysis did not show any classical biochemical features, clinical presentation was suggestive of mitochondrial disease, therefore comprehensive molecular mtDNA analysis was performed. The results revealed single mtDNA deletion of 7.423bp, with 37% of heteroplasmy, confirming the diagnosis of SLSMDs.

Discussion and Conclusion: As seen in our patient, SLSMD can present with atypical symptoms, age discrepancy and evolving phenotype. It is widely known that DM is a most frequent endocrine manifestation of mitochondrial diseases, but its occurrence as an initial symptom, especially at an early age is uncommon. Therefore, identifying patients with mitochondrial disorder among those with DM, particularly in very young children is challenging. As macrocytosis might be the early finding of mitochondrial diseases, this laboratory finding should prompt further metabolic and genetic evaluation after exclusion of the more common causes. Hair and skin changes, when accompanied by other symptoms, should also guide clinicians to a broader diagnostic approach, including mitochondrial pathology. A cluster of symptoms including antibody-negative DM, along with short stature and signs of sporadic dysfunction of organs with high energy demand, suggest a characteristic pattern often observed in mitochondrial disorders.